Our psychological states influence our physical health, not least through their effects on the immune system. Nevertheless, how the nervous and immune systems interact in the context of stress or depression remains an open question. Wheway et al. have investigated the role of neuropeptide Y (NPY), a regulator produced by sympathetic nerves that innervate secondary lymphoid organs. T cells lacking the NPY receptor Y1 responded considerably more vigorously to activation in culture than did Y1-positive T cells. This hyperreactivity was evidenced as an increase in the severity of pathology caused by activating these cells in a mouse model of colitis. In contrast, Y1-deficient mice were themselves relatively resistant to inflammation induced by activated T helper-1 cells, reflecting an apparent defect in dendritic cell (DC) function. One explanation for these seemingly divergent results is that NPY mediates distinct effects on different cells of the immune system. Thus, although T cells can be impeded directly through Y1 receptor signaling, they can also be stimulated indirectly through NPY-assisted activation of the antigen (Ag)-presenting cell function. The mechanistic basis of this dichotomy may further understanding of the neuroimmune interface and yield therapeutic benefits. — SJS